Rett Syndrome (RS) is a neurologic disease affecting only females, characterized by onset between 6-18 months of life of developmental regression, deceleration of head and somatic growth, and profound mental retardation. Pathologic studies of brains from girls with RS have demonstrated small, dysmature brains. There is no evidence of ongoing neurodegeneration or other clastic processes in brain, which has led us to hypothesize that RS is a developmental disorder, causing a disruption of normal brain maturation. Previous studies from the Baylor Rett Center have implicated biogenic monoamines in the pathogenesis of RS, and newly discovered findings in RS cortex have revealed subtle abnormalities in cytoskeletal markers which are consistent with changes in dendritic field development seen by morphologic studies in RS cortex using vital dyes. Furthermore, an increase in the number of white matter neuronal elements in RS has prompted the hypothesis that RS is a disorder of subplate neurons, which are intimately associated with neuronal migration in the developing cortex. In this proposal, we will investigate the role of the monoamine neurotransmitters norepinephrine, serotonin, and dopamine in normal cortical development of the rat, with the goal of creating a neurochemical and neuropathologic model for RS. We will develop paradigms of monoamine deprivation in the rat, and correlate our analyses of these models with known pathologic findings, as well as the proposed studies in Project 2. Our proposal includes studies of cortical cytoarchitecture, neuronal number, and neuronal morphology. From these experiments, we will develop a better understanding of the hypothesized role of monoamines in brain development, and simultaneously work to establish a reproducible model RS pathology.